Chemotherapy with most anticancer agents is complicated by limitations, such as low therapeutic index and host tissue toxicity, which leads to life-threatening situations and decreases the quality of life for many patients. Lack of efficacy and significant potential side effects of standard chemotherapy regimens are driving the search for novel approaches to anticancer therapy. One approach to increase the effectiveness of existing anticancer drugs for cancer treatment is to increase the uptake of drugs into the tumor thereby increasing the therapeutic tumor concentration.
Successful treatment of cancers, including solid tumors, remains an unfulfilled medical goal, despite increased understanding of the molecular biology of tumor cells and the availability of an increased number of potential therapeutic agents. For example, ovarian cancer is the fifth leading cause of cancer deaths in women, the leading cause of death from gynecological malignancy, and the second most commonly diagnosed gynecologic malignancy.
One problem in the treatment of cancers is that an effective dose of a wide variety of potential chemotherapeutic agents is restricted by these agents' non-selective, highly toxic effect on normal tissues. As a result, many patients suffer from the side effects of chemotherapy without reaping the benefits of the treatment. For example, the chemotherapeutic agents cyclophosphamide and cisplatin inhibit cellular proliferation and induces apoptosis of tumor cells. The clinical utility of cyclophosphamide and cisplatin have been hampered, however, by dose limiting toxicities. Thus, there is a necessity to develop more specific and less toxic cancer therapies.
Targeted delivery of chemotherapeutic agents to tumors could have the advantage of enhancing the benefit of chemotherapeutic agents while minimizing their systemic toxic effects. Such targeted delivery could also serve to lower the required dose of chemotherapeutic agents thus potentially reducing the unacceptable adverse effects of these agents. One possible way to achieve targeted delivery of chemotherapeutic agents is to utilize the distinctive features of tumor vasculature.
Tumors greater than a few millimeters in size require a constant nutrient supply, and, therefore, develop their own vascular bed and blood flow (Folkman, Cancer Res, 46:467 (1986)). Without constant nourishment from these developing blood vessels, the tumors become hypoxic and subsequently die. Recruitment of new vasculature from preexisting blood vessels is termed “angiogenesis.”
During angiogenesis, tumor blood vessels develop substantially differently from normal vasculature, and have different properties. Single layered epithelial cells are the first hastily formed tumor blood vessels. These newly formed tumor blood vessels do not have a smooth muscle layer or innervation. Tumors also incorporate mature blood vessels that possess all their autoregulatory functions. Mattsson et al., Tumor Blood Circulation, CRC Press, Boca Raton, pg. 129 (1979); Reinhold, Tumor Blood Circulation, CRC Press, Boca Raton, pg. 115 (1979); Warren, Tumor Blood Circulation, CRC Press, Boca Raton, pg. 26 (1979).
Vascular tone (the degree to which blood vessels are dilated or constricted) is governed by a host of endogenous factors including H+, K+, Ca2+, pO2, pCO2 and nitric oxide (NO), as well as other regulatory substances such as endothelin (ET-1). Secombe et al., Landes, Austin, pg. 40 (1994); Luscher et al., The endothelium: modulator of cardiovascular function, CRC Press, Boca Raton, pg. 61 (1990). ET-1 contributes significantly to regulating vascular tone (Yanagisawa et al., Nature, 332:411 (1988)) and investigators have shown an increase in ET1 and ETB receptor expression in solid tumors including breast carcinomas. Alanen et al., Histopathology, 36:161 (2000); Nelson et al., Cancer Res, 56:663 (1996); Kar et al., Biochem Biophys Res Commun 216:514 (1995); Pagotto et al., J Clin Invest, 96:2017 (1995); Yamashita et al., Cancer Res, 52:4046 (1992); Yamashita et al., Res Commun Chem Pathol Pharmacol, 74:363 (1991). Further, stimulation of ETB receptors causes an increase in blood supply to tumors through vasodilation of tumor blood vessels. The present disclosure takes advantage of this fact by using ETB receptor agonists to selectively increase blood flow to tumors to enhance the targeted delivery of chemotherapeutic agents